Conference Report on Contractures in Musculoskeletal and Neurological Conditions

Received: 31 July 2019 Revised: 3 January 2020 Accepted: 23 February 2020 DOI: 10.1002/mus.26845

ISSUES & OPINIONS

Conference report on contractures in musculoskeletal and neurological conditions

1Division of Neuroscience, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland

2Parent Project Muscular Dystrophy, Hackensack, New Jersey

3The Shirley Ryan AbilityLab, Chicago, Illinois

4Department of Neurology, Stanford University, Palo Alto, California

5School of Pharmacy and Pharmaceutical Sciences, Binghamton University, Johnson City, New York

6Department of Pathology and Laboratory Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin

7Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin

8Physical Therapy and Human Movement Sciences, Northwestern University Feinberg School of Medicine, Chicago, Illinois

9Department of Physical and Occupational Therapy, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

10Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark

11Department of Orthopedic Surgery, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark

12Department of Physical Medicine & Rehabilitation, University of California Davis School of Medicine, Sacramento, California

13Department of Pediatrics, University of California Davis School of Medicine, Sacramento, California

14Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois

15Center for Gene Therapy, Nationwide Children's Hospital, Columbus, Ohio

16Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder, Colorado

17Rusk Rehabilitation, New York University School of Medicine, New York, New York 18Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island

19Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts

20Department of Orthopaedic Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois

21Physical Therapy Department, College of Public Health and Health Professions, University of Florida, Gainesville, Florida

22Department of Rehabilitation, Seattle Children's Hospital, Seattle, Washington

23Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida

Abbreviations: CP, cerebral palsy; DMD, Duchenne muscular dystrophy; ECM, extracellular matrix; EIM, electrical impedance myography; LMN, lower motor neuron; ROM, range of motion; UMN, upper motor neuron.

Correspondence Glen H. Nuckolls, PhD, National Institute of Abstract Neurological Disorders and Stroke, 6001 Limb contractures are debilitating complications associated with various muscle and Executive Blvd, Bethesda, MD 20892. Email: [email protected] nervous system disorders. This report summarizes presentations at a conference at the Shirley Ryan AbilityLab in Chicago, Illinois, on April 19–20, 2018, involving researchers Funding information This workshop was supported by National and physicians from diverse disciplines who convened to discuss current clinical and Institute of Child Health and Human preclinical understanding of contractures in Duchenne muscular dystrophy, stroke, Development, National Institute of Neurological Disorders and Stroke, Parent cerebral palsy, and other conditions. Presenters described changes in muscle architec- Project Muscular Dystrophy, and Shirley Ryan ture, activation, extracellular matrix, satellite cells, and muscle fiber sarcomeric structure AbilityLab that accompany or predispose muscles to contracture. Participants identified ongoing and future research directions that may lead to understanding of the intersecting factors that trigger contractures. These include additional studies of changes in muscle, tendon, joint, and neuronal tissues during contracture development with imaging, molecular, and physiologic approaches. Participants identified the requirement for improved biomarkers and outcome measures to identify patients likely to develop contractures and to accurately measure efficacy of treatments currently available and under development.

KEYWORDS cerebral palsy, contracture, Duchenne muscular dystrophy, muscle, stroke

1 | PURPOSE OF THE WORKSHOP factors are present. Joint pain can be a predictor and/or consequence of contractures in some patients.4,5 Contractures cause significant burden on A research conference was held at the Shirley Ryan AbilityLab in patients due to altered body positioning, decreased independence in per- Chicago, Illinois on April 19–20, 2018, to discuss the causes and treat- forming activities of daily living, and reduced community participation con- ments of contractures, debilitating consequences of a wide range of tributing to social isolation and decreased quality of life. conditions including primary myopathies such as Duchenne muscular dystrophy (DMD), and neurological conditions that affect muscle such as stroke and cerebral palsy (CP). Presenters from the meeting are 3 | CONTRACTURES IN DMD authors of this article. The goals of the meeting were to promote dis- cussion and collaboration among researchers with diverse expertise, Muscular dystrophies are associated with muscle weakness and the gain insights into the causes of contractures, assess biomarkers and replacement of muscle by fat and fibrotic tissue, which contributes to current treatments, and identify gaps in understanding that, if contractures in some patients.2 Researchers studying the natural history addressed, could lead to more effective evidence-based treatments. of DMD discussed data on the patterns of contracture involvement and progression. Altered gait biomechanics resulting from weakness in knee and hip extensors increases the risk that individuals will develop ankle 2 | CONTRACTURES AND PATIENT equinus contracture prior to loss of ambulation, but wheelchair reliance IMPACT is most frequently the result of muscle weakness rather than contractures.6 Contractures develop in the hips and knees in individuals who are There is no universally accepted definition of limb contracture, but reduced nonambulatory when static positioning is more prevalent and weakness range of motion (ROM) accompanied by increased mechanical resistance does not allow full movement against gravity.6-8 Subsequent upper at the ends of the available range are accepted clinical signs. Contractures extremity weakness leads to static positioning and contractures in the in neuromuscular conditions are associated with reduced muscle belly elbows and wrists. The inability of muscles to move a joint through the length, while tendon length is less affected.1-3 Among the neurological and full ROM predisposes the joint to contracture.2 Imbalance in the strength musculoskeletal conditions associated with contracture, the effects on of opposing agonist and antagonist muscles may contribute to this inabil- muscle vary. Some conditions cause muscle hyperactivity, while others ity in some conditions, although in DMD there is no association between cause paralysis or degeneration of muscle fibers and replacement by muscle strength imbalance around a joint and contracture frequency or noncontractile tissue. Muscle weakness or hyperactivity can increase joint severity.6 Contracture progression in DMD is further complicated by static positioning, which may trigger contractures if other predisposing muscle fiber degeneration and tissue fibrosis.2 Mouse models of NUCKOLLS ET AL. 3 muscular dystrophies exhibit progressive muscle weakness and some angles that determine ROM and contracture severity. Video-based exhibit muscle fibrosis, but dystrophic mice do not develop obvious con- motion analysis is also used to measure ROM. Other clinical devices tractures. Presenters described considerable variability in contracture for- used to measure muscle biomechanical properties were discussed, mation in people living with DMD. For example, 50% of participants in including the myotonometer to measure muscle tone for individuals an ongoing study of MRI biomarkers developed knee contractures >20 with UMN signs.14 Ultrasound can measure tendon and muscle kine- soon after loss of ambulation; however, 20% of participants maintained matics, in particular fascicle length and pennation angle in real time full ROM. (R. Willcocks, unpublished data, collected 2010-2018, commu- during static and dynamic tasks. Ultrasound shear wave elastography nicated June 2019). Additional studies are required to identify genetic provides an indirect estimate of tissue stiffness in localized muscle and/or environmental factors that allow some patients to avoid regions.15 Electrical impedance myography (EIM), which assesses the contractures. muscle-induced alteration in a surface-applied current, is sensitive to myofiber cross-sectional area16 and thus has the potential to measure myofiber deformability during passive or active stretch, which 4 | CONTRACTURES IN NEUROLOGICAL could be valuable in assessing contracture severity and response to CONDITIONS therapy. Magnetic resonance imaging and MR spectroscopy have been used to measure muscle volumes, fascicle length, pennation Contractures are associated with upper motor neuron (UMN) disor- angle, fat accumulation, edema, fibrosis, and remaining contractile ders (eg, CP, stroke) and lower motor neuron (LMN) disorders (eg, tissue. Other MR techniques such as magnetization transfer, spin– Charcot Marie Tooth disease). Weakness is common in UMN and lattice relaxation in the rotating frame, diffusion tensor imaging, and LMN disorders. The limb muscles of patients with UMN disorders the use of contrast agents may provide more information about con- often exhibit spasticity, the velocity-dependent increase in tonic tracted muscle. stretch reflexes that can lead to muscle overactivation or As previously discussed, defects in the regulation of sarcomere num- coactivation of antagonistic muscles resulting in muscle stiffness. ber and length may contribute to contractures. A method for measuring However, spasticity is neither sufficient nor required for contrac- sarcomerelengthwithlaserdiffractioninpatientswithCPundergoing tures to develop.9 surgery has provided valuable information.17 With this method, the A- Cellular and extracellular matrix (ECM) changes in muscle associated bands within muscle fibers act as a diffraction grating to incident laser with contractures were discussed. Studies of tissue obtained from light, and diffraction spacing represents sarcomere length. The technique patients with CP provide evidence that the population of muscle- currently requires access to muscle by incision, but work is underway to regenerating satellite cells is decreased by 60% to 70% in contracted adapt this technique to a needle/small probe.18 Additional development muscle.10 Furthermore, the capacity of theremainingsatellitecellsto and research application of contracture-relevant outcome measures and generate muscle cells is diminished owing to epigenetic changes that biomarkers are anticipated. affect expression of myogenic genes.11 The ECM sheaths that separate muscle fibers exhibit increased collagen accumulation in contracted muscle, contributing to tissue stiffness.12 6 | THERAPEUTIC STRATEGIES Presenters also discussed the ability of healthy muscle to adjust the number of sarcomeres per myofibril to optimize filament overlap for Discussions of therapeutic strategies for contractures addressed force production, achieving a proper sarcomere “setpoint.” In individuals mechanical treatments (stretching, splinting, and surgical lengthening) with CP, sarcomere setpoint regulation appears disrupted because mus- as well as pharmacologic approaches. Data were presented from a cle fascicle lengths can be normal while the number of sarcomeres is sig- large natural history study in DMD, revealing that 87% of individuals nificantly reduced. Sarcomeres at longer than optimal lengths may utilize stretching for contracture prevention or treatment, with or contribute to contracture pathogenesis.13 This disrupted sarcomere without use of orthoses (R. Willcocks, unpublished data, collected setpoint phenomenon has not been observed in mice or nonhuman pri- 2010-2018, communicated June, 2019). Even though stretching mates. Additional research is required to understand mechanisms that increases muscle extensibility, stretching regimens performed over regulate sarcomere number and to determine whether disruption of this periods of months appear not to have clinically important effects on regulation is common to conditions other than CP. joint ROM.19,20 Increases in muscle extensibility after stretching pro- grams up to 8 weeks may be due to decreased perception of pain from stretching, resulting in acceptance of greater torque applica- 5 | MEASUREMENT OF CONTRACTURES tion.21 Beneficial physiological effects of stretching unrelated to AND BIOMARKERS ROM, such as changes in blood flow to the muscle or decreased dis- comfort, have not been adequately studied. In addition, the effective- Participants at the meeting presented data on the measurement of ness of stretching regimens carried out over longer periods is musculoskeletal anatomy, joint ROM, musculoskeletal tissue archi- unknown. tecture, composition, and biomechanics in relation to contractures. Nonsurgical treatments that are administered with the goals of The goniometer is the primary instrument used to measure the joint improving or preventing further loss of joint ROM also include serial 4 NUCKOLLS ET AL. casting and night splints in children with DMD or spasticity.22,23 Bet- types in contractures may lead to novel drugs or biologics for contrac- ter understanding of the effects of these treatments on muscle and ture prevention or treatment. tendon architecture through studies with ultrasound or MRI may lead to enhancements in their efficacy. An important perspective was presented at the meeting by the 7 | FUTURE DIRECTIONS mother of a young man living with DMD. She described her son's struggles when attempting to comply with recommendations for daily Discussions at the meeting identified areas of ongoing and future stretching and the use of orthotics to prevent contracture develop- research that may contribute to the level of understanding of contrac- ment. While parents are willing to do whatever will help their child, tures required to advance prevention and treatment strategies. To she asked that experts prescribe regimes based on their professional better understand the mechanisms of contracture development, addi- judgement and the best available information. Physicians and physical tional studies are required on therapists should inform patients of the uncertainty of whether these conservative treatments can prevent or affect contracture • The changes in muscle, tendon, and joint tissues leading up to and progression.19,20 associated with contractures by using available technologies Surgical interventions for contractures focus on helping patients including MRI, ultrasound, or EIM to determine fascicle length, maintain function and comfort. Two studies were presented on out- pennation angle, and sarcomere number and length, muscle, and comes after transverse gastrocnemius-soleus recession for equinus tendon biomechanical properties and ECM composition in the con- gait in children with CP.24,25 In each study, statistically and clinically ditions for which these parameters have not yet been analyzed significant benefits were found when transverse gastrocnemius-soleus • Proliferative and regenerative capacity or fibrotic potential of pro- recession was targeted to appropriate patients. In DMD, there is con- genitor cells in muscle and tendon associated with contractures sensus that foot or Achilles tendon surgery may improve gait in boys • Neurologic activity contributing to spasticity, weakness, altered with significant ankle contracture who are ambulatory and have proprioception, joint pain, and loss of dexterity that are predictors maintained proximal lower limb strength.26 Boys with severe ankle of contractures contracture tend to have insufficient strength to warrant surgery. Sur- • Developing improved animal models of contracture or understanding gery for contractures in nonambulatory patients with DMD is not rec- what makes existing models of disease resistant to contractures. ommended except to address pain or improve wheelchair positioning.26 To better understand why some patients develop contractures Several drugs and biologics were discussed that are being explored early and others do not develop contracture until much later or not at for their effects in preventing or treating contractures. Studies in ani- all, additional studies are required of mal models of contracture have provided evidence that hyaluronan accumulation in the ECM may alter the viscoelastic properties of mus- • The genetic factors associated with contractures within the same cle, contributing to contracture.27 Results were presented from a pre- musculoskeletal or neurological condition and across different liminary study28 of treatment with intramuscular hyaluronidase, an conditions enzyme that degrades ECM hyaluronan in patients with upper limb • Environmental factors such as level of activity/static positioning, muscle stiffness and spasticity after cerebral injury who were at risk of pain management, and the effects of long term stretching and developing contractures. In this study, researchers demonstrated other physical therapy regimens reduced muscle stiffness and increased passive and active joint move- • Prognostic and disease progression biomarkers based on imaging, ment, which persisted 3 to 5 months after treatment. Recent work has musculoskeletal tissue composition, electrophysiological measures, provided imaging evidence of hyaluronan accumulation in patients biomechanical properties, or body fluid biomolecules. with muscle stiffness after cerebral injury, which changes after treatment with hyaluronidase.29 Also discussed was the follistatin analog Knowledge gained through these research avenues can inform FST-288. When it was injected intramuscularly in combination with the optimization of existing surgical and nonsurgical treatments to lessen stretching in a mouse model of immobilization-induced contractures, the impact of contractures, and these studies may identify targets for the this compound promoted longitudinal muscle growth.30 development of novel treatments or preventative measures. Research on strategies to address contracture-associated defects in muscle regeneration were also discussed. Satellite cell-derived myo- ACKNOWLEDGMENTS blasts cultured from contracted muscle of patients with CP exhibited The authors thank Thomas Cheever, PhD (NIAMS/NIH) and Ralph reduced fusion and DNA methylation-dependent inhibition of pro- Nitkin, PhD (NICHD/NIH) for their efforts in planning the conference myogenic signaling pathways. Studies provided evidence that and contributing to this summary and Carsten Bönnemann, MD 5-azacytidine, a drug that alters epigenetic programming, largely (NINDS/NIH) for insightful comments on this meeting summary. This reversed the fusion deficits of CP myoblasts and restored gene workshop was supported by NICHD, NINDS, PPMD and SRAlab. This expression patterns consistent with promyogenic states.11 Further article summarizes the research findings presented and topics dis- characterization of the defects in muscle and connective tissue cell cussed at the meeting. NUCKOLLS ET AL. 5

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